Molecular Mechanisms Associating Chronic Pain with Fatigue, Affective Disorders, Cardiovascular Disease and Total Comorbidity

Project Information

PainFACT

Grant agreement ID: 848099

DOI

10.3030/848099

Project closed

EC signature date 22 November 2019

Start date 1 January 2020

End date 31 December 2025

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost

€ 7 464 296,25

EU contribution

€ 6 000 000,00

Coordinated by

FOLKEHELSEINSTITUTTET
Norway

Periodic Reporting for period 4 - PainFACT (Molecular Mechanisms Associating Chronic Pain with Fatigue, Affective Disorders, Cardiovascular Disease and Total Comorbidity)

Reporting period: 2024-07-01 to 2025-12-31

Summary of the context and overall objectives of the project

Chronic pain is a common health problem with major impact on quality of life and functioning. It is the leading cause of disability and societal costs due to productivity loss are huge, - far greater than those of cardiovascular disease, diabetes, or cancer. The causes of chronic pain are poorly understood, symptomatic treatment efficacy is poor, and curative treatment is lacking for most chronic pain condition. The sheer number of persons affected also presents a challenge and there is a need to find screening methods for early identification of patients at risk of developing severe disabling chronic pain. Notably, chronic pain patients also tend to suffer from additional conditions, including anxiety, depression, fatigue, cardiovascular diseases and premature mortality. The full extent of this clustering of diseases with chronic pain is unknown, and the mechanisms causing these conditions to cluster together remain to be identified.

The overall objective of PainFACT is therefore to identify patterns of disease that co-occur with chronic pain and to identify the mechanisms that cause these diseases to occur together. Through analysis of patient data from the population of an entire country, PainFACT aims to identify medical conditions that are associated with chronic pain. Using state-of-the-art, genetic techniques, measurements of proteins in blood, and brain imaging analysis in humans and mice, PainFACT will identify mechanisms and develop predictive models for chronic pain and related conditions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

PainFACT has been executed in overlapping discovery and validation phases with analysis of human and animal data. Key to the discovery phase is the analysis of very large datasets. In humans this encompasses analysis of the clustering of diseases using health registry data for the entire Norwegian population with more than 5M individuals, genetic analysis of large population-based studies, such as UK-Biobank (500k) and Danish Bloodbank (500k), and analysis of blood proteins, brain imaging, and extensive clinical examinations that are available in the Rotterdam Study and Tromsø Study. Importantly this also includes measurements of pain sensitivity – the largest dataset accumulated to date with more 30,000 participants tested. In animal models, a large discovery sample of nearly 300 outbred mice were exposed to either chronic pain or sham treatment with measurement of pain sensitivity, anxiety, depression, memory, metabolic markers, atherosclerosis, brain imaging and gene expression in the brain and spinal cord. Follow-up analysis and validation of findings have been conducted by cross-validation across human cohorts, longitudinal analysis, and more specialized techniques, such as Mendelian randomization studies. A key molecular finding from genetic analysis of pain sensitivity has been tested in animal models where the gene is removed, and resultant effects on pain, comorbid conditions and brain structure and function are observed.

In total the project has held 16 invited presentations at international conferences and published 15 papers, with additional papers submitted or in press. Among these, is a study of the genetics of back-pain (Bjornsdottir, et al. 2022, Nature Communications), identifying 41 genetic variants; and a study identifying the 26 genetic risk loci for fibromyalgia (Kerrebijn, et al., In review). Aside from migraine, the genetics of pain has lagged behind other fields, and getting a grip on the genetics of other common pain outcomes is of central importance for understanding the molecular mechanisms of pain.

Nevertheless, most findings from the study have yet to be disseminated and cannot be shared publicly before they have undergone peer review and publication. Without going into specifics, these findings show that PainFACT has successfully identified novel molecular mechanisms of pain and that these mechanisms also impact comorbid conditions, such as cardiovascular disease, in line with the overall hypothesis of the study.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Some key results of the project:

1. PainFACT has confirmed and expanded on existing knowledge of pain comorbidity. In particular the project has been able to identify some pain conditions as conferring a high risk of cardiovascular disease. This information will be of value to clinicians and affected patients as they suggest that closer monitoring of this patient group is mandated.

2. PainFACT has conducted the first large-scale genetic study of pain sensitivity, identifying five genetic loci associated with pain tolerance, some of which point to concrete mechanisms that also involve comorbid conditions, such as anxiety and depression. These findings provide a new inroad into understanding the biology of pain and potential new drug targets for pain treatment.

3. PainFACT has conducted extensive brain imaging studies in humans and mice, revealing relationships between brain structure and pain, and marked sex differences in the way that pain is processed in the brain. As part of this work, new magnetic resonance imaging analysis software has been developed and approved for clinical use.

4. PainFACT has developed algorithms based on proteins measured in blood that successfully predict pain sensitivity, as well as some of the key comorbidities of pain. While further work is needed, this indicates that screening tools can be developed for potential use in clinical practice.

5. PainFACT has revealed that the biological mechanisms of pain can be identified through large scale studies using genetics, protein analysis and related techniques. As such, it is a proof of concept and a call for further research into this highly impactful health problem.

The focus of PainFACT is on mechanisms and basic science, and as such the project is not directed at creating change at a societal level. However, chronic pain is the leading cause of disability and arguably the single most expensive health-care problem, and it is likely that the PainFACT project will have some impact at a societal level. In the short term, identifying biological predictors of pain may help remove the stigma that many pain patients experience, since many still find that their suffering is not believed or that it is reframed as a psychiatric problem. Identifying patients at risk of developing future severe pain or of developing comorbid cardiovascular disease is also likely to change the way these patients are met and treated by the health-care system. In the long term, and with further research, our hope is that PainFACT results and methods will contribute to the development of new pain treatments that are effective without being addictive and potentially also help prevent comorbid conditions.

The PainFACT consortium partners gathered at the kick-off meeting 8 January 2020

The PainFACT project group gathered at deCODE's premises in Reykjavik 16 June 2023.

PainFACT Infographic - Discovery - Validation - Integration